Myelin: High Speed

Neurons, the “gray matter” in the brain, rightly deserve their reputation as masters of computation. But only once they are clad in white do they also perform communication wonders. To exchange information with many, many other neurons, nerve cells need axons. Through these “data cables,” they make contact with one another and form extensive networks. In doing so, they span distances of up to several meters – a huge distance in the cellular cosmos. To accomplish this, axons need either a considerable diameter or good insulation. The solution in vertebrates is insulation via myelin, a particularly fatty and therefore white-appearing, electrically insulating biomembrane. It wraps around the axons. But how does the Myelin sheath get around the axons? And what exactly does it do there? 

What at first glance appears to be a boring sheath turns out, upon closer inspection, to be a fascinating, dynamic, and highly complex phenomenon. Immediately after birth, much of the newborn’s brain is still a gray blur. The myelination of the axons – which gives the “white matter” in the brain and Spinal cord its name – begins during pregnancy, but continues throughout childhood and is further refined during puberty. And myelination even continues beyond that – albeit to a much lesser extent.

Specialized cells called Oligodendrocytes are responsible for this insulation process. Each of these cells, which belong to the glial cell family, can wrap cellular projections around several axonal segments on different axons, much like a bandage. In this way, oligodendrocytes also function as cable ties, bundling multiple axons together. They also supply the Axon and its many energy-hungry ion pumps with nutrients.

The Myelin sheaths provide a truly dramatic speed boost to the electrical signals – the action potentials – that travel along the Axon from the cell body to the synapses at the other end of the cell. Without myelin, such an Action potential propagates by gradually changing the voltage at the cell membrane along the entire length of the axon. When a certain threshold is exceeded, voltage-gated membrane channels open, allowing a sudden influx of positively charged sodium ions into the cell. As a result, the Membrane potential at this point shoots up even further, pushing the region further downstream past the threshold as well, so that the voltage-gated channels there also open. The action potential thus travels to the end of the axon via a chain reaction.

However, this process proceeds relatively slowly, at a speed of about one meter per second. Warmer temperatures or a larger axon diameter – where there is more electrically conductive internal volume per unit of membrane surface area, and thus reduced longitudinal resistance – can accelerate the journey. Some mollusks, such as squid and sea snails, use this strategy to transmit particularly fast signals via exceptionally thick axons – up to one millimeter in diameter – even without myelination.

In vertebrates, and thus also in the human brain, however, myelin ensures greater speed – while simultaneously saving a great deal of space in the highly complex central nervous system. Above all, it allows the electrical signal to simply skip over myelinated sections of the axon. Thanks to the insulating effect, the action potential generated locally can propagate relatively undisturbed as an electric field within the axon. This is sufficient to reach the threshold for opening the voltage-gated channels at the next gap where the cell membrane is exposed – the Ranvier node. The action potential now jumps at breakneck speed from one node to the next, enabling an enormous conduction speed – up to 100 meters per second.

Despite this sophisticated insulation strategy, when it comes to transmission speed, “size matters.” It depends on the thickness of the axon beneath the myelin as well as its thickness at the intervening nodes. The thickness of the myelin sheath itself and the length of the wrapped sections also play a role.

Benedikt Grothe of Ludwig Maximilian University of Munich was researching signal transmission in the auditory system, where milliseconds often make the difference in distinguishing subtle differences between sounds ▸ The Secret to Successful Communication. Through experiments and modeling, he has discovered that the fastest possible signal transmission occurs when the axon diameter is large and the myelin segments are short. However, this maximum speed comes at a cost, since with many short, isolated segments, the number of nodes along the fiber also increases – points at which the action potential must actively jump from one segment to the next – a process that requires a great deal of energy. “In practice, we therefore often observe a trade-off between speed and metabolic cost,” says Grothe. “But if the circuit demands it, the speed can be maximized.” These factors can also vary along a single axon. Toward the end of the axon, for example, the researchers observe an increasing optimization of axon diameter and myelin segment length geared toward speed. This presumably serves as a safeguard to ensure that the action potential reliably reaches the synapse.

The Myelin sheath is thus more than just insulation. Rather, it is a highly precise configuration of the Axon and the surrounding Oligodendrocytes. And this configuration is by no means rigid. “Changes in myelination have much in common with neural plasticity, even if the processes take months rather than days,” says Tim Czopka, who by now moved with his research group from the Technical University of Munich to the University of Edinburgh. Together with his team, he is studying zebrafish to investigate how myelination changes in response to the activities and experiences of individual neurons. In humans, too, it can be observed that intensive and long-term learning processes affect the White matter in the brain. For example, when learning to juggle or play a new instrument, the white matter increases in certain regions; specific neural circuits become more heavily myelinated to improve signal transmission in those areas. “The connections between neurons via synapses are just one level of communication within a network, but for the impulses to arrive at the right place at the right time, myelination must also be adjusted,” says Czopka.

Once an axon is fully wrapped, it can still make some fine adjustments together with its oligodendrocytes – for example, changing its diameter or adjusting the length of the myelinated segments and the position of the myelin sheaths. However, other forms of Plasticity are then no longer possible. For example, it can no longer form axonal branches once it is encased in its “corset.” Czopka therefore suspects that the most exciting events take place wherever parts of the axon are not yet – or are no longer – myelinated. In these areas, there are many opportunities for neurons and oligodendrocytes to find their individual configuration through interaction with one another and in response to activity within the system.

Communication begins when the oligodendrocyte precursor cells go in search of partners. Inspired by signals that have largely remained unknown until now, the cells then scan their environment for suitable neurons. “They try to wrap themselves around everything they can with their stubby extensions, like little spiders,” explains Czopka, who films these processes live in the transparent larvae of zebrafish (see box). Depending on the signals they detect in the vicinity of a specific axon, they either stabilize their extensions or retract them.

It is already becoming clear that the interaction between the two cell types is very finely tuned. Oligodendrocytes and their precursors themselves have many receptors for neurotransmitters and voltage-gated ion channels, which they use to “listen” to the activity of neurons. If a nerve cell is very active, the metabolic activity of the oligodendrocytes surrounding it also changes: they divide and differentiate more rapidly. Understanding the exact nature and dynamics of these signals is one of the research goals of Czopka and his team.

Behind these research efforts lies the hope of being able to better restore the balance between neurons and oligodendrocytes in the future, after it has been disrupted – for example, by disease or injury. In ▸ multiple sclerosis, for example, misdirected immune cells attack the oligodendrocytes and destroy the Myelin sheath – at least temporarily. This jeopardizes both the neurons’ energy supply and their communication with other nerve cells. Depending on the course of the disease, however, the system can recover at least partially and regenerate destroyed myelin sheaths. The hope is that one day, through targeted intervention in the development and activity of oligodendrocytes, it will be possible to precisely repair the function of neural networks.

Further reading

• Ford MC et al: Tuning of Ranvier node and internode properties in myelinated axons to adjust action potential timing.  Nature Communications, 2015, 6:8073 ( zum Volltext )
• Marisca R et al: Functionally Distinct Subgroups of Oligodendrocyte Precursor Cells Integrate Neural Activity and Execute Myelin Formation.  Nat Neurosci. 2020 Mar; 23(3): 363–374. ( zum Volltext )